Browsing by Author "Morgan, Gareth"

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    Differential RNA splicing as a potentially important driver mechanism in multiple myeloma
    (Ferrata Storti Foundation, 2021-03-01) Bauer, Michael A.; Ashby, Cody; Wardell, Christopher; Boyle, Eileen M.; Ortiz, Maria; Flynt, Erin; Thakurta, Anjan; Morgan, Gareth; Walker, Brian A.; Medicine, School of Medicine
    Disruption of the normal splicing patterns of RNA is a major factor in the pathogenesis of a number of diseases. Increasingly research has shown the strong influence that splicing patterns can have on cancer progression. Multiple Myeloma is a molecularly heterogeneous disease classified by the presence of key translocations, gene expression profiles and mutations but the splicing patterns in MM remains largely unexplored. We take a multifaceted approach to define the extent and impact of alternative splicing in MM. We look at the spliceosome component, SF3B1, with hotspot mutations (K700E and K666T/Q) shown to result in an increase in alternative splicing in other cancers. We discovered a number of differentially spliced genes in comparison of the SF3B1 mutant and wild type samples that included, MZB1, DYNLL1, TMEM14C and splicing related genes DHX9, CLASRP, and SNRPE. We identified a broader role for abnormal splicing showing clear differences in the extent of novel splice variants in the different translocation groups. We show that a high number of novel splice loci is associated with adverse survival and an ultra-high risk group. The enumeration of patterns of alternative splicing has the potential to refine MM classification and to aid in the risk stratification of patients.
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    Identifying 1q amplification and PHF19 expressing high-risk cells associated with relapsed/refractory multiple myeloma
    (Research Square, 2023-08-16) Johnson, Travis S.; Sudha, Parvathi; Liu, Enze; Blaney, Patrick; Morgan, Gareth; Chopra, Vivek S.; Dos Santos, Cedric; Nixon, Michael; Huang, Kun; Suvannasankha, Attaya; Abu Zaid, Mohammad; Abonour, Rafat; Walker, Brian A.; Biostatistics and Health Data Science, School of Medicine
    Multiple Myeloma is an incurable plasma cell malignancy with a poor survival rate that is usually treated with immunomodulatory drugs (iMiDs) and proteosome inhibitors (PIs). The malignant plasma cells quickly become resistant to these agents causing relapse and uncontrolled growth of resistant clones. From whole genome sequencing (WGS) and RNA sequencing (RNA-seq) studies, different high-risk translocation, copy number, mutational, and transcriptional markers have been identified. One of these markers, PHF19, epigenetically regulates cell cycle and other processes and has already been studied using RNA-seq. In this study a massive (325,025 cells and 49 patients) single cell multiomic dataset was generated with jointly quantified ATAC- and RNA-seq for each cell and matched genomic profiles for each patient. We identified an association between one plasma cell subtype with myeloma progression that we have called relapsed/refractory plasma cells (RRPCs). These cells are associated with 1q alterations, TP53 mutations, and higher expression of PHF19. We also identified downstream regulation of cell cycle inhibitors in these cells, possible regulation of the transcription factor (TF) PBX1 on 1q, and determined that PHF19 may be acting primarily through this subset of cells.
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    International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease
    (American Society of Clinical Oncology, 2013-06-20) Terpos, Evangelos; Morgan, Gareth; Dimopoulos, Meletios A.; Drake, Matthew T.; Lentzsch, Suzanne; Raje, Noopur; Sezer, Orhan; Garcıa-Sanz, Ramon; Shimizu, Kazuyuki; Turesson, Ingemar; Reiman, Tony; Jurczyszyn, Artur; Merlini, Giampaolo; Spencer, Andrew; Leleu, Xavier; Cavo, Michele; Munshi, Nikhil; Rajkumar, S. Vincent; Durie, Brian G.M.; Roodman, G. David; Department of Medicine, IU School of Medicine
    PURPOSE: The aim of the International Myeloma Working Group was to develop practice recommendations for the management of multiple myeloma (MM) -related bone disease. METHODOLOGY: An interdisciplinary panel of clinical experts on MM and myeloma bone disease developed recommendations based on published data through August 2012. Expert consensus was used to propose additional recommendations in situations where there were insufficient published data. Levels of evidence and grades of recommendations were assigned and approved by panel members. RECOMMENDATIONS: Bisphosphonates (BPs) should be considered in all patients with MM receiving first-line antimyeloma therapy, regardless of presence of osteolytic bone lesions on conventional radiography. However, it is unknown if BPs offer any advantage in patients with no bone disease assessed by magnetic resonance imaging or positron emission tomography/computed tomography. Intravenous (IV) zoledronic acid (ZOL) or pamidronate (PAM) is recommended for preventing skeletal-related events in patients with MM. ZOL is preferred over oral clodronate in newly diagnosed patients with MM because of its potential antimyeloma effects and survival benefits. BPs should be administered every 3 to 4 weeks IV during initial therapy. ZOL or PAM should be continued in patients with active disease and should be resumed after disease relapse, if discontinued in patients achieving complete or very good partial response. BPs are well tolerated, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw. Kyphoplasty should be considered for symptomatic vertebral compression fractures. Low-dose radiation therapy can be used for palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression. Orthopedic consultation should be sought for long-bone fractures, spinal cord compression, and vertebral column instability.
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    Multi-Institutional US Experience of the Occlutech© AFR Device in Congenital and Acquired Heart Disease
    (Tech Science Press, 2021) O’Callaghan, Barry; Zablah, Jenny; Vettukattil, Joseph; Levi, Daniel; Salem, Morris; Cabalka, Allison; Anderson, Jason; Ebeid, Makram; Alexy, Ryan; Morgan, Gareth; Pediatrics, School of Medicine
    Objectives: To detail the US multi-institutional experience with the Occlutech© (Occlutech International AB, Helsingborg, Sweden) atrial flow regulator (AFR) in children and adults with acquired or congenital heart disease. Background: The creation of a long-term atrial communication is desirable in several cardiovascular disease phenotypes, most notably pulmonary arterial hypertension, disorders of increased left ventricular filling and increased cavopulmonary pressures in patients with a Fontan type circulation. Methods: Patients were identified for inclusion from the AFR device manufacturer database. Data was collected using a RedCap database following IRB approval. 8 weeks of follow up data was sought for each patient based on available data. Data was analyzed and summarized using SPSS. Results: We report the experience of 6 US centers in the implantation of AFR devices in 15 patients, across a wide age range, with different disease phenotypes and a variety of indications. Implantation was technically successful in all patients and improvement was noted in both clinical and hemodynamic parameters. There were no immediate or intermediate term complications reported. 3 patients died remote from implantation. Their deaths were not felt to be related to the AFR device or related procedural complications. Conclusion: Compassionate use of the AFR device in children and adults with congenital & acquired heart disease is technically feasible and produces beneficial short term hemodynamic and symptomatic improvement. Widespread uptake of this technique and treatment at specialist centers has the potential to provide significant benefits to a variety of complex patients with currently limited treatment options and indeterminate prognosis.
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    Real-world comparative effectiveness of triplets containing bortezomib (B), carfilzomib (C), daratumumab (D), or ixazomib (I) in relapsed/refractory multiple myeloma (RRMM) in the US
    (Springer, 2021) Davies, Faith; Rifkin, Robert; Costello, Caitlin; Morgan, Gareth; Usmani, Saad; Abonour, Rafat; Palumbo, Antonio; Romanus, Dorothy; Hajek, Roman; Terpos, Evangelos; Cherepanov, Dasha; Stull, Dawn Marie; Huang, Hui; Leleu, Xavier; Berdeja, Jesus; Lee, Hans C.; Weisel, Katja; Thompson, Michael; Boccadoro, Mario; Zonder, Jeffrey; Cook, Gordon; Puig, Noemi; Vela-Ojeda, Jorge; Farrelly, Eileen; Raju, Aditya; Blazer, Marlo; Chari, Ajai; Medicine, School of Medicine
    Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optum's deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.
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    Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities
    (Springer Nature, 2021-03-25) Oben, Bénedith; Froyen, Guy; Maclachlan, Kylee H.; Leongamornlert, Daniel; Abascal, Federico; Zheng-Lin, Binbin; Yellapantula, Venkata; Derkach, Andriy; Geerdens, Ellen; Diamond, Benjamin T.; Arijs, Ingrid; Maes, Brigitte; Vanhees, Kimberly; Hultcrantz, Malin; Manasanch, Elisabet E.; Kazandjian, Dickran; Lesokhin, Alexander; Dogan, Ahmet; Zhang, Yanming; Mikulasova, Aneta; Walker, Brian; Morgan, Gareth; Campbell, Peter J.; Landgren, Ola; Rummens, Jean-Luc; Bolli, Niccolò; Maura, Francesco; Medicine, School of Medicine
    Multiple myeloma (MM) is consistently preceded by precursor conditions recognized clinically as monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). We interrogate the whole genome sequence (WGS) profile of 18 MGUS and compare them with those from 14 SMMs and 80 MMs. We show that cases with a non-progressing, clinically stable myeloma precursor condition (n = 15) are characterized by later initiation in the patient’s life and by the absence of myeloma defining genomic events including: chromothripsis, templated insertions, mutations in driver genes, aneuploidy, and canonical APOBEC mutational activity. This data provides evidence that WGS can be used to recognize two biologically and clinically distinct myeloma precursor entities that are either progressive or stable.